AKT deficiency alters dopamine sensitivity in the prefrontal cortex ABSTRACT Schizophrenia is a devastating psychiatric syndrome that affects up to 1% of the human population. Understanding the pathophysiological processes underlying this disease is essential for improving treatment. Recently, impairment of the AKT signaling pathway has been implicated in the pathophysiology of schizophrenia. Although AKT is known to be important for dopaminergic transmission to maintain normal functioning of the prefrontal cortex, whether and how impairment of AKT affects the dopamine system are not clearly understood. Using an approach integrating electrophysiology and biochemistry, this proposal seeks to examine our hypothesis that cortical AKT deficiency alters dopamine sensitivity by beta-arrestin 2-mediated mechanisms. We will first examine whether and how disruption of AKT changes dopamine sensitivity to inhibitory synaptic transmission in the PFC. We will examine the responses inhibitory synaptic transmission to different concentrations of dopamine or different types of dopamine receptor agonists under conditions of pharmacologic blockage and RNA interference knockdown of AKT. We predict a shift of dopamine sensitivity to inhibitory synaptic transmission. Next, we will explore the mechanisms underlying the AKT deficiency-induced shifting of dopamine sensitivity. We hypothesize that AKT deficiency will alter the affinity of beta-arrestin by disrupting the protein complexes, thus affecting dopamine sensitivity. We will first explore whether AKT deficiency increases dopamine receptor internalization by examining surface number of dopamine receptors. We will then test whether AKT deficiency-induced decrease in dopamine sensitivity changes with loss of beta- arrestin 2. Next, we will test whether AKT deficiency-induced decrease in DA sensitivity is involved in changes in phosphorylation or protein level of beta-arrestin 2. Finally, we will examine whether interaction of beta- arrestin 2 with clathrin and dopamine receptors is enhanced by AKT deficiency. This proposal will offer novel information for a better understanding of dopaminergic regulation of synaptic communication between neurons whose functioning is related to mental disorders.